Mobile phone-based interventions for improving adherence to medication prescribed for the primary prevention of cardiovascular disease in adults

Types of studies

We will include randomised controlled trials (RCTs) of parallel group design that randomise by participant or by cluster. We will not include cross-over trials as this design would be inappropriate for assessing effects on cardiovascular events or mortality, due to the irreversible of these events. We will only include trials with a minimum of one-year follow-up in order that the outcome measures relate to longer-term, sustained medication adherence behaviours and outcomes. We will include studies published as full text and as abstract only, and unpublished data.

Types of participants

We will include adults (aged 18 years and over) who have been prescribed medication for the primary prevention of CVD. As this review will focus on the primary prevention of CVD, we will only include studies involving participants who have not had a prior CVD event, defined as: a previous myocardial infarction (MI), stroke, revascularisation procedure (coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI)), people with angina, and people with angiographically defined CHD. Where we identify trials that include a subset of eligible participants, we will contact the authors to request data for only those participants of interest. In the event that we are unable to access these data, we will apply a cut-off whereby only trials in which at least 75% of participants meet the criteria for primary prevention will be included.

Types of interventions

We will include trials of interventions delivered wholly or partly by mobile phone to improve adherence to cardiovascular medications prescribed for the primary prevention of CVD. We will include interventions targeting adherence to antihypertensive drugs (thiazide-like diuretic, angiotensin-converting enzyme (ACE) inhibitor, calcium channel blocker, beta-blocker); lipid-lowering drugs (statins); and antiplatelet drugs (low-dose aspirin, non-aspirin antiplatelet drugs). We will only include trials targeting adherence to at least one of these medications. We will also include trials of interventions that target medication adherence alongside other lifestyle modifications.

Intervention: any mobile phone-specific delivery mechanism, including short messaging service (SMS), multimedia messaging (MMS), applications (apps) and Interactive Voice Response (IVR). We will include interventions employing a mix of delivery mechanisms of which at least one is mobile phone-based, for example, interventions delivered by mobile phones in combination with traditional methods such as face-to-face communication and links to other types of support (e.g. healthcare support worker, telephone calls, web pages).

Comparator: usual care and active controls where the control group intervention has no component delivered by a mobile phone-specific delivery mechanism.

Types of outcome measures

Electronic searches

We will identify trials through systematic searches of the following bibliographic databases from inception to the date of search:

• Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library;

• MEDLINE (Ovid);

• Embase (Ovid);

• CINAHL Plus (EBSCOhost);

• Conference Proceedings Citation Index-Science (CPCI-S) on Web of Science (Thomson Reuters).

The preliminary search strategy for MEDLINE (Ovid) (Appendix 1) will be adapted for use in the other databases. The Cochrane sensitivity-precision maximising RCT filter (Lefebvre 2011) will be applied to MEDLINE (Ovid) and adaptations of it to the other databases, except CENTRAL.

We will carry out a search of ClinicalTrials.gov (www.ClinicalTrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) Search Portal (apps.who.int/trialsearch/) for ongoing or unpublished trials.

We will impose no restriction on language of publication.

We will not perform a separate search for adverse effects of mobile phone-based interventions targeting medication adherence. We will consider adverse effects described in included studies only.

Searching other resources

We will check the reference lists of all included studies and we will review relevant articles for additional references. We will also examine any relevant retraction statements and errata for included studies.

Selection of studies

Two review authors (MP and SB) will independently screen the titles and abstracts of all identified potential studies to decide whether to retrieve the full text (eligible or potentially eligible/unclear studies) or to discard the study. Two review authors (MP and SB) will independently screen the retrieved full texts to identify studies for inclusion and identify and record reasons for exclusion of the ineligible studies in a 'Characteristics of excluded studies' table. We will endeavour to resolve any disagreements though discussion, and if necessary, a third review author (CF or PP) will arbitrate. We will exclude any duplicates. Multiple reports of the same RCT study will be collated into a single entry. We will complete a PRISMA flow diagram.

Data extraction and management

We will use a standardised, prepiloted form to extract data from the included studies for assessment of study quality and evidence synthesis. We will contact chief investigators for additional information if necessary. We will extract the following information.

• Methods: study design; total duration of study; study setting and date of study.

• Participants: number randomised; number lost to follow-up/withdrawn; number analysed; mean age; age range; gender; proportion meeting criteria of 'primary prevention'; and inclusion criteria and exclusion criteria.

• Interventions: intervention; comparison; concomitant medications; excluded medications; intervention delivery mechanism (text messages/MMS/mobile application/combined); how intervention was developed; behaviour change technique(s) employed; if intervention was personalised; and frequency and duration of intervention receipt.

• Outcomes: primary and secondary outcomes specified and collected; adverse effects; and time points reported.

• Notes: funding for trial and notable conflicts of interest of trial authors.

Two review authors (MP and SB) will independently extract data and resolve any differences by returning to the original study reports and discussion with a third review author (CF or PP) where necessary. One review author (MP) will transfer data into the Review Manager 5 (RevMan 2014). To ensure that there are no errors in data entry, one review author (SB) will check that the data entered into Review Manager 5 are consistent with those in the data extraction form.

Assessment of risk of bias in included studies

Two review authors (MP and SB) will independently assess the risk of bias for each study using the criteria detailed in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). For each of the following domains, we will grade the potential bias as high, low or unclear.

• Random sequence generation.

• Allocation concealment.

• Blinding of participants and personnel.

• Blinding of outcome assessment.

• Incomplete outcome data.

• Selective outcome reporting.

• Other biases.

We will resolve any disagreements by discussion. Where necessary, we will consult a third review author (CF or PP) to arbitrate. We will construct a 'Risk of bias' table including justifications for our judgements. Where information relating to the risk of bias has come from unpublished data or correspondence with an author, we will note this. We will summarise the risk of bias judgements across different studies for each of the domains listed. When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.

Given the nature of the interventions to be included in this review, it is likely that blinding of participants and personnel will be impossible, therefore, we expect trials to be categorised at high risk of bias on this domain. For the overall study assessment, we will categorise a trial as being at low risk of bias if it was rated as low risk in all the domains listed above (with the exception of blinding of participants and personnel). Trials that have been rated as high or unclear risk of bias on any of the domains (except blinding of participants and personnel) will be categorised as being at high risk of bias.

Measures of treatment effect

We will analyse dichotomous outcome data as risk ratios with 95% confidence intervals. We will analyse continuous outcome data as mean differences with 95% confidence intervals, or if a continuous outcome has been measured in multiple ways, as a standardised mean difference with 95% confidence intervals. We will enter data presented as a scale with a consistent direction of effect. We will report any skewed data identified as medians and interquartile ranges.

Unit of analysis issues

We will include RCTs with parallel design. If we identify cluster RCTs for inclusion, we will analyse the data accounting for clustering using the intracluster coefficient (ICC).

If we identify multi-arm trials for inclusion, where there is more than one relevant intervention arm but only one control arm, the intervention arms will be pooled for a single pair-wise comparison as recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will exclude intervention arms not appropriate for this review.

Dealing with missing data

We will contact investigators or study sponsors to obtain missing data where possible (e.g. when a study is identified as abstract only). Where this is not possible, and the missing data are considered a potential source of serious bias, we will conduct a sensitivity analysis to explore the impact of including such studies in the overall assessment of results.

Assessment of heterogeneity

We will use the I² statistic to measure heterogeneity across the trials for the analysis of each outcome. Where we identify there to be moderate to substantial heterogeneity (an I² statistic between 30% and 100%), we will report it and examine possible causes according to our prespecified subgroup analyses.

Assessment of reporting biases

If the results from more the 10 trials can be pooled, we will use a funnel plot to explore possible small-study biases for the primary outcomes.

Data synthesis

We will carry out meta-analyses only if it considered meaningful to do so (i.e. if the interventions, participants and outcome measures are similar enough for pooling to make sense). In the absence of heterogeneity, we will use fixed-effect models. In the presence of heterogeneity (an I² statistic in excess of 30%), we will provide a narrative overview without pooling data for analysis.

Subgroup analysis and investigation of heterogeneity

If there are sufficient studies, we will carry out the following subgroup analyses for the primary outcome of adherence to treatment:

• income region (by World Bank income group) (World Bank 2017);

• how text messages were developed (i.e. theory-based, incorporating user views and based on evidence relating to factors influencing behaviour-targeted versus other);

• intervention content (number behaviour change technique employed coded according to the taxonomy developed by Michie and colleagues (Michie 2015));

• delivery mechanisms (i.e. mobile phone messaging only, mobile applications only, combined mobile phone messaging and application, combined application and other).

We will use the formal test for subgroup interactions in Review Manager 5 (RevMan 2014).

Sensitivity analysis

We plan to carry out the following sensitivity analyses.

• Only including studies with low risk of bias.